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Status dystonicus (SD) is a rare and potentially life-threatening condition requiring intensive care management. Deep brain stimulation (DBS) has emerged as an effective treatment for SD refractory to medical management, but its application in this field is still limited. Here, we report the long-term outcome of four pediatric patients treated with DBS at the University Hospital of Padua, Italy, for SD refractory to medications. In addition, we present the results of a systematic literature review aimed at identifying published cases of SD treated with DBS, with focus on motor outcome. In our cohort, two children were affected by methylmalonic acidemia and suffered acute basal ganglia lesions, while the other two carried a pathogenic mutation in GNAO1 gene. DBS target was subthalamic nucleus (STN) in one case and globus pallidus internus (GPi) in three. All patients experienced SD resolution within 8–19 days after surgery. Mean post-operative follow-up was 5 years. We identified in the literature 53 additional SD cases treated with DBS (median age at DBS implantation: 12 years) with reported positive outcome in 51 and resolution of SD in a mean of 17 days after surgery. Our findings indicate that DBS is an effective treatment for SD refractory to medications, even in patients with acute basal ganglia lesions; STN can be an appropriate target when GPi is damaged. Moreover, data from long-term follow-up show that SD recurrences can be significantly reduced in frequency or abolished after DBS implantation.

Objective Large intradural growth of tympanojugular paragangliomas (TJ-PGs) into the cerebellopontine angle is an infrequent condition that can determine an extensive involvement of vessels and brainstem, representing a surgical challenge. The current classifications lack accuracy for defining large intradural TJ-PGs and assessing their operability. This study aims to retrospectively reappraise the management of a large intradural TJ-PGs surgical series, discussing operability criteria, treatment strategies, and resection techniques. Methods Over a series of 63 class D TJ-PGs operated on between 1973 and 2008, patients with large intradural tumors were retrospectively reviewed. Surgical techniques and outcomes with long-term follow-up were analyzed. Results Seven patients presented with large intradural tumors, ranging from 4 cm to 5.5 cm in diameter. These cases were treated either via a petro-occipital transsigmoid approach in a single-stage resection (4 patients) or via a petro-occipital approach as a second-stage surgery after a previous infratemporal fossa approach on the extradural tumor (3 patients). Complete tumor resection was obtained in 5 cases through wide removal of the petro-occipital skull base and exposure of the dural root of the tumor, which carries its main blood supply and allows preemptive hemostasis. No new postoperative cranial nerve losses were observed. The surgical procedure was aborted in 2 cases because of cerebellar edema and carotid artery tear, respectively. Conclusions Large intradural TJ-PGs can be effectively surgically managed with an appropriate technique combined with relevant nonsurgical strategies. Thus, operability criteria for these lesions can be extended. To share objective experience on large intradural TJ-PGs, a redefinition of Di3 tumors is recalled.

Deregulation of intracellular signal transduction pathways is a hallmark of cancer cells, clearly differentiating them from healthy cells. Differential intracellular distribution of the cAMP-dependent protein kinases (PKA) was previously detected in cell cultures and in vivo in glioblastoma and medulloblastoma. Our goal is to extend this observation to meningioma, to explore possible differences among tumors of different origins and prospective outcomes. The distribution of regulatory and catalytic subunits of PKA has been examined in tissue specimens obtained during surgery from meningioma patients. PKA RI subunit appeared more evenly distributed throughout the cytoplasm, but it was clearly detectable only in some tumors. RII was present in discrete spots, presumably at high local concentration, these aggregates could also be visualized under equilibrium binding conditions with fluorescent 8-substituted cAMP analogues, at variance with normal brain tissue and other brain tumors. The PKA catalytic subunit showed exactly overlapping pattern to RII and in fixed sections could be visualized by fluorescent cAMP analogues. Gene expression analysis showed that the PKA catalytic subunit revealed a significant correlation pattern with genes involved in meningioma. Hence, meningioma patients show a distinctive distribution pattern of PKA regulatory and catalytic subunits, different from glioblastoma, medulloblastoma, and healthy brain tissue. These observations raise the possibility of exploiting the PKA intracellular pathway as a diagnostic tool and possible therapeutic interventions.

Purpose: In-depth characterization of recurrent glioblastoma (rGBM) might contribute to a better understanding of the mechanisms behind tumor progression and enable rGBM treatment with targeted drugs. Experimental Design: In this study, GBM samples were collected at diagnosis and recurrence from adult patients treated with Stupp protocol. Expression of mismatch repair (MMR) proteins was evaluated by IHC, followed by whole exome sequencing (WES) of tumor samples showing loss of MSH6 reactivity. Established genetic, epigenetic, and immunologic markers were assessed by standard methods and correlated with loss of MMR proteins and patient survival. Results: Expression of MMR proteins was partially or completely lost in 25.9% rGBM samples. Specifically, 12 samples showed partial or total MSH6 expression reduction. Conversely, 96.4% of GBM samples at diagnosis expressed MMR markers. WES disclosed lack of variants in MMR genes in primary samples, whereas two MSH6-negative rGBM samples shared a c.3438+1G>A* splicing MSH6 variant with a potential loss of function effect. MSH6-negative rGBM specimens had high tumor mutational burden (TMB), but no microsatellite instability. In contrast, GBM samples with partial loss of MMR proteins disclosed low TMB. MMR-deficient rGBM showed significant telomere shortening and MGMT methylation and are characterized by highly heterogeneous MHC class I expression. Conclusions: Multilevel profiling of MMR-deficient rGBM uncovered hypermutated genotype uncoupled from enriched expression of immune-related markers. Assessment of MHC class I expression and TMB should be included in protocols aiming to identify rGBM patients potentially eligible for treatment with drugs targeting immune-checkpoint inhibitors.

I ntroduction Vagus nerve stimulation (VNS) is a neuromodulation technique approved for Treatment-Resistant Depression (TRD).Evidence regarding its long-term efficacy and safety is still scarce. Objectives To descriptively report a case series of 3 patients undergoing adjunctive VNS for TRD with an over 10-year follow-up. Methods We investigated outcomes of clinical interest in patients with ongoing VNS for at least 10 years after the device implantation. They had participated in a larger single-arm interventional study conducted at the University Hospital of Padua. They were diagnosed with chronic unipolar (1), recurrent unipolar (1), and bipolar (1) TRD. Results Our 3 cases had an average 14-year history of psychiatric disease before surgery. Afterward, all subjects achieved clinical remission within two years. 2 patients experienced relapses within the first 4 years of treatment (respectively, 1 and 2 episodes). The other case showed a recurrent trend of brief relapses every two years. Only 1 individual needed to be admitted to the psychiatric unit once. None of them committed suicidal attempts. Prescription of antidepressants remained almost unchanged after the first two years. 2 individuals improved and 1 maintained their working position. Common adverse events were voice alteration (3/3), neck pain (2/3), and cough (2/3). Conclusions Very few cases of 10-year VNS for TRD have been reported so far. For our subjects, VNS was most likely to have a major impact on the clinical course of the disease. This treatment can be a safe and effective adjunctive intervention in a subgroup of patients with TRD.

Highlights • DTI and performance data on three task-switching paradigms were collected on young adults. • Frontal inter-hemispheric white matter integrity favors sustained task-switching. • This result was observed when switching between spatial rules or color-shape ones. • No relation between behavior and white matter was observed for verbal rule switching. • Task-specific features determine whether white matter mediates task-switching performance., The capacity to flexibly switch between different task rules has been previously associated with distributed fronto-parietal networks, predominantly in the left hemisphere for phasic switching sub-processes, and in the right hemisphere for more tonic aspects of task-switching, such as rule maintenance and management. It is thus likely that the white matter (WM) connectivity between these regions is critical in sustaining the flexibility required by task-switching. This study examined the relationship between WM microstructure in young adults and task-switching performance in different paradigms: classical shape-color, spatial and grammatical tasks. The main results showed an association between WM integrity in anterior portions of the corpus callosum (genu and body) and a sustained measure of task-switching performance. In particular, a higher fractional anisotropy and a lower radial diffusivity in these WM regions were associated with smaller mixing costs both in the spatial task-switching paradigm and in the shape-color one, as confirmed by a conjunction analysis. No association was found with behavioral measures obtained in the grammatical task-switching paradigm. The switch costs, a measure of phasic switching processes, were not correlated with WM microstructure in any task. This study shows that a more efficient inter-hemispheric connectivity within the frontal lobes favors sustained task-switching processes, especially with task contexts embedding non-verbal components.

The optimal treatment of recurrent glioblastoma (GBM) in elderly patients is unclear. Fotemustine (FTM) is a third-generation nitrosourea showing efficacy in gliomas and it has been used with different schedules in adult patients. We performed, for the first time anywhere, a mono-institutional retrospective study to analyze the clinical outcome of an alternative fotemustine schedule in elderly patients with recurrent GBM. Retrospectively, we analyzed all GBM patients 65 years or older previously treated with the combination of radiation therapy and temozolomide (TMZ), receiving an alternative FTM schedule as second-line treatment at our Oncological Center from October 2011 to October 2014 with an ECOG PS ≤ 2. FTM was administrated at 80 mg/m(2) every 2 weeks for five consecutive administrations (induction phase), and then every 4 weeks at 80 mg/m(2) as maintenance. We enrolled 44 patients, 33 males and 11 females; average age was 70 years. ECOG PS was 0-1 in 80 % of the patients. 38 patients relapsed during temozolomide (TMZ) therapy. MGMT methylation status was analyzed in 34 patients and MGMT was methylated in 53 % of the patients. The median progression free survival (PFS) and overall survival (OS) from FTM treatment was 4.1 months (95 % CI 3.1-5.2) and 7 months (95 % CI 5.2-8.4), respectively. Patients with MGMT methylated status and patients who relapsed after completing TMZ therapy had a longer PFS and OS from the beginning of FTM. Thrombocytopenia was the most frequent grade 3-4 haematological toxicity (9 %). The alternative schedule of FTM may be an active and safe treatment for elderly patients with recurrent glioblastoma, especially patients with methylated MGMT and who relapsed after completing temozolomide therapy.

Disease prognosis is very poor in patients with brain tumors. Cognitive deficits due to disease or due to its treatment have an important weight on the quality of life of patients and caregivers. Studies often take into account quality of life as a fundamental element in the management of disease and interventions have been developed for cognitive rehabilitation of neuropsychological deficits with the aim of improving the quality of life and daily-life autonomy of patients. In this literature review, we will consider the published studies of cognitive rehabilitation over the past 20 years.

Anaplastic Astrocytoma(AA) is a malignant, diffusely infiltrating, primary brain tumor. According to the WHO 2016 classification of central-nervous-system tumors, AA has been described as a glial tumor with no co-deletion of 1p/19q, and is divided into IDH mutated tumor, characterized by better prognosis, and IDH wild-type form, with worse prognosis. The standard of care is maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Several efforts have been made to evaluate, according to molecular selection, which is the best post-surgical treatment. At recurrence, the treatment remains challenging and some trials are ongoing to evaluate new potential drugs, alone or in combination with chemotherapy. We performed a description of the status of the art on diagnosis, molecular characteristics and treatment of AA. In particular, we focused our details on new drugs; indeed, a deeper knowledge of the molecular characteristics of gliomas could lead to to development of active personalized treatments according with precision medicine.

Despite network studies of the human brain have brought consistent evidence of brain regions with diverse functional roles, the neuropsychological approach has mainly focused on the functional specialization of individual brain regions. Relatively few neuropsychological studies try to understand whether the severity of cognitive impairment across multiple cognitive abilities can be related to focal brain injuries. Here we approached this issue by applying a latent variable modeling of the severity of cognitive impairment in brain tumor patients, followed by multivariate lesion-symptom methods identifying brain regions critically involved in multiple cognitive abilities. We observed that lesions in confined left lateral prefrontal areas including the inferior frontal junction produced the most severe cognitive deficits, above and beyond tumor histology. Our findings support the recently suggested integrated albeit modular view of brain functional organization, according to which specific brain regions are highly involved across different sub-networks and subserve a vast range of cognitive abilities. Defining such brain regions is relevant not only theoretically but also clinically, since it may facilitate tailored tumor resections and improve cognitive surgical outcomes.

BACKGROUND: GC is defined as a rare pattern of growth of gliomas, involving three or more cerebral lobes. Considering its rarity, it’s still difficult to define prognostic factors and standard of treatment. Retrospectively, we analyzed patients (PT) with GC from two neuro-oncology centers to identify main prognostic factors and the optimal management. MATERIAL AND METHODS: Medical records of patients ≥ 18years, with histological and/or radiological diagnosis of GC occurred between 2006 and 2017 were reviewed. Median progression free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method. RESULTS: We analyzed 33PT, 22males and 11female; ECOG performance status (PS) was 0–1 in 21PT and ≥ 2 in 12PT. 22PT underwent biopsy: 16 were astrocytomas, 6oligodendrogliomas. MGMT was detected in 14PT: it was metilated in 8cases. IDH1 was analyzed in 16PT: it was mutated in 10PT. 15 of 33PT showed localized enhancing lesions at diagnosis. 9PT(27%) were treated with radiation therapy (RT) plus concurrent temozolomide (TMZ), 22PT(67%) received only TMZ, and 2PT(6%) underwent RT alone. Best response was complete response (CR) in 3PT(3%), partial response (PR) in 9PT(27%) and stable desease (SD) for 15PT(45%); only 8PT(25%) had a progression desease (PD). For all PT, PFS and OS were 19.1 and 30.7 months (ms) respectively. For PS 0–1 and ≥2, PFS was 34.6 vs 3.4ms (p

Pediatric patients with circumscribed cerebellar pilocytic astrocytoma (PA) tumors generally perform within the normal range on neuropsychological tests after a complete tumor resection. The outcome in academically relevant abilities such as mathematics, which in adults involve some cerebellar functions, is however much less understood. The aim of this study is to retrospectively investigate the neuroplasticity of mathematical skills and associated cognitive functions following cerebellar resection of PA in pediatric patients. Twenty-two children (mean age = 11.2 + 1.8), including 11 PA patients (females = 6) and 11 healthy controls (females = 6), were administered a battery of mathematical (MaT) and neuropsychological tests. Single-case statistical analyses were carried out (Crawford’s t) as well as between-group comparisons (Wilcoxon test). Spearman correlations between MaT and neuropsychological tests were calculated. Thirty-six percent of the patients showed difficulties in some mathematical tasks, 50% of them within a broader cognitive deficit. Verbal working memory was associated with MaT performance both in patients and controls while, crucially, visuospatial memory, and visual-motor integration were associated with MaT in patients only. Among patients, MaT correlated negatively with tumor size and positively with the interval surgery test. The results evince an overall recovery of mathematical abilities despite PA in the majority of patients. This functional reestablishment is supported by visuospatial and visuomotor integration functions that contribute to set up emerging mathematical skills in these patients. Higher levels of compensation are found in more developed tumors as compared to smaller ones.

Purpose: We report our preliminary experience concerning the use of thrombin-gelatin hemostatic matrix to strengthen the final hemostasis after posterior fossa low-grade tumor surgery in children. To our knowledge, this is the first report regarding the use of hemostatic matrix in pediatric neurosurgery. Materials and Methods: Between 2012 and 2016, twenty-three patients underwent posterior fossa surgery for low-grade gliomas in our department. The mean age was 6.35 years; 12 patients were female and 11 male. Histology revealed pilocytic astrocytoma in 15 cases, ependymoma in 7 cases, and gangliocytoma in 1 case. At the end of the surgery, effective hemostasis was achieved using standard methods and, in order to strengthen the final hemostasis, we used a thrombin-gelatin hemostatic matrix. In all of the cases a postoperative MRI was performed within 24 after the surgery; during hospitalization the patients underwent a clinical evaluation. Moreover, blood samples were taken to evaluate inflammatory parameters, hemoglobin, and sodium, and kidney and liver tests were performed according to the standard protocol. Results: The postoperative MRI did not show any complications imputable to the matrix. Dur ing radiological and clinical follow-up none of the patients showed any delayed complications related to the matrix. Conclusions: In our practice we found thrombin-gelatin hemostatic matrix sealant to be a valid and safe tool for strengthening hemostasis in pediatric low-grade posterior fossa surgery.

The current treatment options for acoustic neuromas (AN) - observation, microsurgery and radiotherapy - should assure no additional morbidity on cranial nerves VII and VIII. Outcomes in terms of disease control and facial function are similar, while the main difference lies in hearing. From 2012 to 2016, 91 of 169 patients (54%) met inclusion criteria for the present study, being diagnosed with unilateral, sporadic, intrameatal or extrameatal AN up to 1 cm in the cerebello-pontine angle; the remaining 78 patients (46%) had larger AN and were all addressed to surgery. The treatment protocol for small AN included observation, translabyrinthine surgery, hearing preservation surgery (HPS) and radiotherapy. Hearing function was assessed according to the Tokyo classification and the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) classification. Sixty-one patients (71%) underwent observation, 19 (22%) HPS and 6 (7%) translabyrinthine surgery; 5 patients were lost to follow-up. Median follow-up was 25 months. In the observation group, 24.6% of patients abandoned the wait-and-see policy for an active treatment; the risk of switching from observation to active treatment was significant for tumour growth (p = 0.0035) at multivariate analysis. Hearing deteriorated in 28% of cases without correlation with tumour growth; the rate of hearing preservation for classes C-D was higher than for classes A-B (p = 0.032). Patients submitted to HPS maintained an overall preoperative hearing class of Tokyo and AAO-HNS in 63% and 68% of cases, respectively. Hearing preservation rate was significantly higher for patients presenting with preoperative favourable conditions (in-protocol) (p = 0.046). A multi-option management for small AN appeared to be an effective strategy in terms of hearing outcomes.Opzioni di terapia vs osservazione per i piccoli neurinomi dell’acustico: una gestione orientata alla funzione uditiva.Le opzioni di trattamento per il neurinoma del nervo acustico (AN), ovvero osservazione, microchirurgia e radioterapia non dovrebbero esporre a una morbidità addizionale i nervi cranici VII e VIII. Esse comportano risultati simili su controllo del tumore e conservazione del nervo facciale, ma differenti e discussi quanto a udito. Dal 2012 al 2016, 169 pazienti con diagnosi di AN sporadico, monolaterale sono stati valutati nel nostro centro. In totale, 91 pazienti hanno soddisfatto i criteri di inclusione, presentando un tumore intracanalare o extrameatale di dimensioni inferiori a 1 cm in angolo pontocerebellare. I restanti 78 pazienti con AN di dimensioni maggiori sono stati tutti trattati con opzione chirurgica primaria. La funzione uditiva è stata determinata sulla base delle classificazioni di Tokyo e dell’American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). Il controllo post trattamento ha avuto una durata media di 25 mesi. Sessantuno pazienti (71%) sono andati incontro a trattamento conservativo di osservazione, 19 (22%) a chirurgia di preservazione dell’udito (HPS) e 6 (7%) a chirurgia per via translabirintica; 5 pazienti sono stati esclusi per incompletezza di dati. Il 24,6% dei pazienti in osservazione è uscito da tale protocollo durante il follow-up. Il rischio di cambiare da osservazione a trattamento attivo è risultato significativo all’analisi multivariata per i tumori in crescita (p = 0,0035). Nello stesso gruppo in osservazione, l’udito è andato incontro a un peggioramento nel 28% dei casi, indipendentemente da una correlazione con la crescita tumorale. La conservazione di un udito in classe A-B si è dimostrata significativamente inferiore rispetto a quella per un udito in classe C-D (p = 0,032) nel tempo di osservazione. I pazienti sottoposti a HPS hanno mantenuto la classe uditiva preoperatoria nel 63% e nel 68% dei casi, rispettivamente per le classificazioni di Tokyo e AAO-HNS. Il tasso di preservazione dell’udito inoltre, si è dimostrato significativamente maggiore per i pazienti che si presentavano con caratteristiche preoperatorie più favorevoli (in-protocol) (p = 0,046). Un protocollo di trattamento multi-opzionale per i piccoli AN rappresenta una strategia efficace per il risultato chirurgico a breve termine.

Current imaging modalities enable early diagnosis of a large number of small acoustic neuromas in patients with well-preserved hearing, whose best management is still a debatable matter. Comparing the hearing outcome of the various therapeutical approaches, including observation, radiosurgery, or resective surgery, is not easy because of the numerous classifications measuring hearing in different ways. In this review, a literature review was performed and papers selected dealing with small tumors, short- and long-term hearing, tumor control or radical resection, and effect of pre-treatment hearing and size on outcome. Two different surgical institutional series of sporadic vestibular schwannomas provided us comparative data on the outcome of observation alone. Our experience suggests that active treatment with hearing preservation surgery, unlike observation alone, offers a better chance of hearing preservation, also enabling a more effective treatment of the tumor and an appropriate rehabilitation with hearing aids or cochlear implants.

Intraparenchymal cavities communicating with the ventricles may appear in patients with chronic obstructive hydrocephalus despite no identifiable surgerical, vascular or traumatic causes. The rate, features, pathogenesis, evolution and clinical impact of intraparenchymal diverticula have not been outlined, yet. Brain MRIs of 130 patients (mean age: 11.3 years; age range: 0–67; 60 females) with chronic obstructive hydrocephalus were analyzed. The pathogenesis, neurosurgical treatment, ventricle size, signs of transependymal reabsorption and septum pellucidum integrity of the hydrocephalus were recorded. Subarachnoid outpouching of the ventricles, post-hemorrhagic parenchymal cavities, paths of ventricular shunting and cavities not communicating with the ventricles were excluded. Of patients with intraparenchymal diverticula, all previous available CT and MRI scans were evaluated. Eight patients (6.2 %, mean age: 18.7 years; age range: 2–42) harbored 11 intraparenchymal diverticula sprouting from the temporal (6), occipital (3) or frontal (2) horns of the lateral ventricles. Intraparenchymal diverticula were more frequent in males (p = 0.04) and older patients (18.7 ± 12.7 vs 11.3 ± 9.8 years, p = 0.04). Their presence or evolution (mean neuroradiological follow-up 3.6 years; range: 0–8) showed a trend of association with hydrocephalus severity (bifrontal index) and did not correlate with the surgical treatment. In three patients the diverticula progressed during follow-up. One patient presented with hemiparesis consistent with the intraparenchymal lesion and improved after ventricular shunting. A DTI study revealed that the cortico-spinal tract was partly included in the septum between the ventricle and the intraparenchymal diverticulum. Clinicians dealing with chronic severe obstructive hydrocephalus should be aware of ventricular intraparenchymal diverticulation. Studies aiming at clarifying their pathogenesis and proper management are warranted.

Pharmacogenomics, the science of how genetic makeup influences an individual's reaction to drugs, is an innovative tool for providing critical insights into how a patient will respond to a particular treatment. In the present work, we constructed cancer-like tissues to be used as tools for determining the most effective drug for an individual patient. Using tissue engineering strategies, we generated two different solid tumor-like tissues in vitro, a neuronal tumor (meningioma) and a nonmelanoma skin cancer. Samples were tested by both histological and genetic approaches (using a comparative genomic hybridization array, and the relative World Health Organization classification of the samples was compared with the results obtained by the molecular analyses. Our data confirmed the ability of the cells to maintain their phenotype in three-dimensional scaffolds as well as the strong relationship between chromosomal alterations and histological malignancy grades. We then validated the in vitro construction of tumor-like tissues as a potential tool for developing personalized drug treatments.

The ability to shift between different tasks according to internal or external demands, which is at the core of our behavioral flexibility, has been generally linked to the functionality of left fronto-parietal regions. Traditionally, the left and right hemispheres have also been associated with verbal and spatial processing, respectively. We therefore investigated with functional MRI whether the processes engaged during task-switching interact in the brain with the domain of the tasks to be switched, that is, verbal or spatial. Importantly, physical stimuli were exactly the same and participants' performance was matched between the two domains. The fMRI results showed a clearly left-lateralized involvement of fronto-parietal regions when contrasting task-switching versus single task blocks in the context of verbal rules. A more bilateral pattern, especially in the prefrontal cortex, was instead observed for switching between spatial tasks. Moreover, while a conjunction analysis showed that the core regions involved in task-switching, independently of the switching context, were localized both in left inferior prefrontal and parietal cortices and in bilateral supplementary motor area, a direct analysis of functional lateralization revealed that hemispheric asymmetries in the frontal lobes were more biased toward the left side for the verbal domain than for the spatial one and vice versa. Overall, these findings highlight the role of left fronto-parietal regions in task-switching, above and beyond the specific task requirements, but also show that hemispheric asymmetries may be modulated by the more specific nature of the tasks to be performed during task-switching.

Brain tumor glioblastoma has no clear molecular signature and there is no effective therapy. In rodents, the intracellular distribution of the cyclic AMP (cAMP)-dependent protein kinase (Protein kinase A, PKA) R2Alpha subunit was previously shown to differentiate tumor cells from healthy brain cells. Now, we aim to validate this observation in human tumors. The distribution of regulatory (R1 and R2) and catalytic subunits of PKA was examined via immunohistochemistry and Western blot in primary cell cultures and biopsies from 11 glioblastoma patients. Data were compared with information obtained from 17 other different tumor samples. The R1 subunit was clearly detectable only in some samples. The catalytic subunit was variably distributed in the different tumors. Similar to rodent tumors, all human glioblastoma specimens showed perinuclear R2 distribution in the Golgi area, while it was undetectable outside the tumor. To test the effect of targeting PKA as a therapeutic strategy, the intracellular cyclic AMP concentration was modulated with different agents in four human glioblastoma cell lines. A significant increase in cell death was detected after increasing cAMP levels or modulating PKA activity. These data raise the possibility of targeting the PKA intracellular pathway for the development of diagnostic and/or therapeutic tools for human glioblastoma.

Background Although the diagnosis and treatment of eighth cranial nerve (VIII CN) schwannoma (acoustic neuroma) has improved over the years, no factors capable of predicting tumor growth have been identified as yet. This study is a preliminary investigation of the expression in sporadic VIII CN schwannomas of Yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), and amphiregulin (AREG), a direct target gene of YAP and TAZ. The expression of YAP, TAZ and AREG was correlated with the volumetric dimensions of tumors on contrast-enhanced magnetic resonance imaging (ceMRI). Methods YAP, TAZ and AREG expression was assessed immunohistochemically in surgical specimens of 36 consecutive sporadic VIII CN schwannomas. 3D reconstructions of the tumors and their corresponding volumes in cm3 were obtained from measurements on ceMRI images using the OsiriX® software. Results We found a significant direct correlation between TAZ expression and VIII CN schwannoma volumes on latest preoperative ceMRI (p3 than in those with a volume 3 (pConclusions The immunohistochemical expression of TAZ (but not YAP or AREG) correlated significantly with schwannoma volume measured on ceMRI. Further investigations are needed to identify the biological factors influencing tumor proliferation (ideally secreted proteins like AREG) that might be detected using non-invasive approaches (i.e., blood samples).

The diverging evidence for functional localization of response inhibition within the prefrontal cortex might be justified by the still unclear involvement of other intrinsically related cognitive processes like response selection and sustained attention. In this study, the main aim was to understand whether inhibitory impairments, previously found in patients with both left and right frontal lesions, could be better accounted for by assessing these potentially related cognitive processes. We tested 37 brain tumor patients with left prefrontal, right prefrontal and non-prefrontal lesions and a healthy control group on Go/No-Go and Foreperiod tasks. In both types of tasks inhibitory impairments are likely to cause false alarms, although additionally the former task requires response selection and the latter target detection abilities. Irrespective of the task context, patients with right prefrontal damage showed frequent Go and target omissions, probably due to sustained attention lapses. Left prefrontal patients, on the other hand, showed both Go and target omissions and high false alarm rates to No-Go and warning stimuli, suggesting a decisional rather than an inhibitory impairment. An exploratory whole-brain voxel-based lesion-symptom mapping analysis confirmed the association of left ventrolateral and dorsolateral prefrontal lesions with target discrimination failure, and right ventrolateral and medial prefrontal lesions with target detection failure. Results from this study show how left and right prefrontal areas, which previous research has linked to response inhibition, underlie broader cognitive control processes, particularly involved in response selection and target detection. Based on these findings, we suggest that successful inhibitory control relies on more than one functionally distinct process which, if assessed appropriately, might help us to better understand inhibitory impairments across different pathologies., Highlights • Inhibitory and other co-occurring processes were investigated in brain tumor patients. • Attentional lapses in terms of target misses were observed in right frontal patients. • Decisional impairment concerning response selection was found in left frontal patients. • These results were confirmed by a voxel-based lesion-symptom mapping analysis. • Broader cognitive control deficits can account for errors in inhibitory task contexts.

OBJECTIVE: The pterional approach represents the standard approach for most lesions of the anterior and middle cranial fossa. It requires some degree of frontal lobe retraction, which may result in temporary or permanent damage of olfaction because of nerve avulsion or mechanical compression. The purpose of this study, based on microanatomic dissection of human cadaveric specimens, was to review the microsurgical anatomic features of the nerve and suggest operative nuances that may contribute to reducing the rate of postoperative olfactory dysfunction. METHODS: Twenty olfactory nerves and tracts were examined in 10 human cadaveric heads obtained from three fresh and seven formalin-fixed adult cadavers. A standard pterional craniotomy was performed. The olfactory nerve was dissected from its arachnoidal envelopes and then mobilized for an average length of 30 mm (range, 25–35 mm). RESULTS: The possible retraction of the frontal lobe was 10 to 15 mm. More retraction invariably resulted in nerve disruption. CONCLUSION: The standard sylvian and basal cistern opening may be insufficient to guarantee preservation of olfactory function. Early identification and arachnoidal dissection of the nerve may reduce the rate of olfaction compromise. The opening of the subarachnoidal space should be performed in a proximal-to-distal manner to allow early visualization of the olfactory bulb and its dissection. The arachnoidal dissection should be performed with sharp instruments, avoiding any traction on the posterior portion of the olfactory tract. Any direct retractor compression should also be avoided to spare the microvasculature lying on the dorsal surface of the nerve.

To characterize in vivo the transpedicular approach (TA) as an alternative route to study intervertebral disc (IVD) regeneration strategies in a sheep model.48 IVD of 12 sheep were used. TA was performed under fluoroscopy, followed by nucleotomy (2-mm shaver resector). A polyurethane scaffold was used to repair the end-plate. X-ray and MRI images were acquired pre-, intra- and post-operatively (1, 3, 6 months). Complications were recorded.TA was feasible in all animals; nucleus pulposus (NP) from L1 to L5 was accessible. Nucleotomy followed by end-plate repair was achieved. Loss of NP signal intensity was shown in MRI images of the nucleotomy group.TA is feasible in vivo, repeatable after only a short learning period and safely performed without significant morbidity. This animal model allows the study of IVD degeneration physiopathology and investigation of IVD regeneration techniques in vivo.

The replacement of damaged cells in the central nervous system (CNS) affected by degenerative disorders represents an attractive therapeutic strategy. The advent of stem cell technology may offer the possibility of generating a large number of renewable, specifically differentiated cells to potentially cure large cohorts of patients. In this review, we discuss current knowledge and issues involved in neural cell transplantation. The most important preclinical and clinical results of cellular transplantation applied to Parkinson's, Huntington's disease and amyotrophic lateral sclerosis will be summarized.Cellular transplantation is emerging as a possible therapy for a variety of incurable neurological disorders. The disorders that will primarily take advantage from neural stem cell grafting are those involving a well defined cell population in a restricted area of the CNS. Several clinical trials have been initiated to assess safety and efficacy of different stem cell-derived products, and promising results have been obtained for disorders such as Parkinson's disease. However, several scientific questions remain unanswered. Among these, the impact of the immunological interaction between host and graft in the particular environment of the CNS still requires additional investigations.Several chronic neurological disorders appear to be amenable to cell regenerative therapies. However, safety, efficacy and immunological issues will need to be carefully evaluated beforehand.

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases. However, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation and differentiation. Parkinsonian primates received wild-type or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 months. Recovery was associated with restoration of dopaminergic activity detected both by PET imaging and histological examination. Local infiltration by T-cells and CD80/86-positive microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that, in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T-cell costimulation. This article is protected by copyright.

Background Moyamoya syndrome represents an etiologically heterogeneous cerebral evolutive angiopathy. It can be associated with both well-characterized and recently described genetic conditions with mendelian inheritance. Case report We report the case of a moyamoya angiopathy in a prematurely born girl affected by congenital heart defect, mild facial dysmorphism, mild neurodevelopmental delay and borderline cognitive profile, associated to a de novo complex rearrangement involving the terminal segment of the short arm of chromosome 6. Conclusion To the best of our knowledge, this is the second case described of pediatric moyamoya syndrome associated with a 6p complex rearrangement. Adding this case to the pertinent literature, we discuss the pathogenic role of rearrangements in 6p region in moyamoya syndrome and suggest to investigate in this region potential genes involved in angiogenesis or vascular homeostasis.

Medulloblastoma in adulthood is uncommon but not rare; annual incidence is 2-20/1,000,000. Some peculiarities characterize medulloblastoma in adult patients compared with the child type: lateral cerebellar location, heterogeneous signal intensity on magnetic resonance imaging, desmoplastic histological variant, and more favourable prognosis. Preoperative diagnosis is crucial for correct management of these patients. However, because of the low incidence of medulloblastoma in the adult population, preoperative diagnosis remains challenging and prognostic factors and best treatment options are still controversial. In this setting, some unusual findings, for example multifocal presentation and extra-axial location, can confound diagnosis and make treatment difficult. We present a short case-illustrated review on these remarkable issues.

Malignant gliomas continue to demand the search for improved chemotherapeutic solutions. In this work the results of a preliminary in vitro screening performed on a small library of compounds are disclosed. As a result 2-(2,4-dihydroxyphenyl)-8-hydroxy-1,4-naphthoquinone emerged as a promising therapeutic lead.

The relationship between venous thromboembolism (VTE) and cancer is supported by several pathogenetic factors, including circulating microparticles (MP) originating from different cells and often bearing tissue factor. Since VTE often complicates the clinical course of patients with glioblastoma multiforme (GBM; WHO grade IV astrocytoma) and the role of MPs in these patients population is still not clear, this prospective study was conducted to evaluate the procoagulant activity of circulating MP (MP activity) in GBM patients. We enrolled 61 GBM patients undergoing gross-total or subtotal surgical resection followed by combined radio-chemotherapy; 20 healthy volunteers were tested as controls. Blood samples for MP activity and hemostatic profiles were obtained before and then 1 week and 1, 4, and 7 months after surgery. GBM patients had significantly higher mean MP activity levels than healthy controls before and 7 days after surgery. During the follow-up, MP activity levels became significantly lower 1 and 4 months after surgery (P = 0.007 and P = 0.018, respectively) than prior to surgery, but this decrease was only seen in the subgroup achieving complete tumor resection. MP activity levels increased in 7 (63.6%) of 11 patients who developed VTE. The different incidence of the increase in MP activity levels between patients with and without VTE was statistically significant (χ (2) = 4.93, P = 0.026; relative risk 1.38, 95% CI 1.03-1.86). GBM patients may have an increase in MP-associated procoagulant activity that could contribute to any prothrombotic states and increases the likelihood of VTE complications; this procoagulant activity drops during control of disease.

Medulloblastoma (MDB) is the most common brain malignancy of childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. Although interaction between hypoxia-inducible factor-1α (HIF-1α) and Notch signaling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here, we investigate whether hypoxia, through HIF-1α stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133+ and nestin+ precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with γ-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion.

Carmustine (1,3-bis[2-chloroetyl]-1-nitrosurea (BCNU)) wafers are approved for the local treatment of newly diagnosed and recurrent malignant glioma. Reassuring data on both safety and efficacy of treatment have been previously reported by phase III studies. Although most of related adverse events are reported in the first few months after surgery, there is a lack in the literature of radiological data regarding this period. Few anecdotal experiences have been reported about surgical bed cyst occurrence. The aim of our study is to analyse the radiological course of patients treated with wafers implantation focusing on the relationship between radiological data, and in particular bed cyst occurrence, and safety data.Forty-three patients affected by malignant glioma underwent surgical removal and BCNU wafers implantation at the Department of Neurosurgery of Padova from April 2007 to October 2009. Safety data were collected according to previously reported phase III studies. Patients underwent clinical and radiological evaluation (MRI) postoperatively, then before discharge, at 1 month, then every 2 months. In the study were included only patients whose both 1- and 3-month MRIs were available. Finally, 36 out of 43 patients were available for the revision.Fifty-eight percent of patients treated with BCNU wafers presented a bed cyst of the surgical cave at the 1-month MRI. Forty-eight percent of them were symptomatic. Conversely, among patients who presented one or more adverse event (27%), bed cyst was detected in up to 90% of cases (OR 7.35), being intracranial hypertension more frequently associated (OR 7.35; p value0.05). In general, cysts presented a benign behaviour in the sense that patients promptly improved with corticosteroid treatment, never required surgery, never reported permanent neurological deficits.Surgical bed cyst occurrence in BCNU wafer-treated patients resulted more frequent than expected. Familiarity with the event is important to correctly handle a possible evolving phenomenon. However, only further larger experiences and prospective studies could reveal how the understanding of such event might be helpful to improve safety data.

2012A LARGE, MULTICENTER, RETROSPECTIVE STUDY TO IDENTIFY A CUT-OFF OF MGMT METHYLATION STATUS BY QUANTITATIVE PYROSEQUENCING APPROACH IN PATIENTS (PTS) WITH GLIOBLASTOMA (GBM). Background: MGMT pr...

This study aims to verify the reliability of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) measurements to differentiate benign from atypical/malignant meningiomas and among different sub-types.Pre-operative DWI of 102 patients (74 females, mean age 58 years, age range 34-85 years) affected by a pathologically proven intracranial meningioma were retrospectively reviewed. DWI signal intensity of tumors was classified as hypo-, iso- or hyper-intense to grey matter. ADC values and normalised ADC(ratio) (ADC(meningioma)/ADC(normal appearing white matter)) of the neoplastic tissue (avoiding calcifications and cystic or necrotic areas) were measured by two neuroradiologists unaware of each others' reading. MRI and histological findings were compared.Meningiomas were histologically graded as malignant (1%), atypical (21.5%) and benign (77.5%). Meningothelial, transitional and fibrous were the most frequent benign sub-types (44, 16 and 10 cases, respectively). There was no statistical difference between typical and atypical/malignant meningiomas when considering mean ADC values (0.964 +/- 0.192 x 10(-3) vs 0.923 +/- 0.085 x 10(-3) cm(2)/s, p = 0.3 t-Student) or ADC(ratio) (1.266 +/- 0.290 vs 1.185 +/- 0.115, p = 0.2 t-Student). ADC values or ADC(ratio) did not differ significantly among meningioma sub-types although a nearly significant difference was found between meningothelial and transitional (post hoc analysis p = 0.06). Inter-observer agreement of ADC and ADC(ratio) measurements was high (r = 0.95 and 0.92, respectively, Pearson's linear coefficient). DWI intensity did not reach a significant correlation with meningioma's grading (p = 0.08).According to our study, DWI and ADC measurement do not seem reliable in grading meningiomas or identifying histological sub-types. Hence, these parameters should not be recommended for surgical or treatment planning.

A significant amount of recent interest has been focused on the possibility that adult human stem cells are a realistic therapeutic alternative to embryonic stem cells. Multipotent stem cells that have characteristics reminiscent of embryonic neural crest stem cells have been isolated from several postnatal tissues, including skin, gut, dental pulp and the heart, and are potentially useful for research and therapeutic purposes. However, their neurogenic potential, including their ability to produce electrophysiologically active neurons, is largely unexplored. In the present work, we investigated this issue with regard to skin-derived precursors (SKPs) and adipose-derived stem cells (ADSc)Adult stem cells isolated from skin and from adipose tissue derived from the same adult donor were treated with epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2). Neurospheres obtained were first expanded and evaluated in term of proliferative ability, and then their neuronal differentiation potential was analysed.Adipose- and skin-derived neurospheres grew in suspension as spheres in the presence of the mitogens FGF2 and EGF. With this protocols, the spheres have been able to proliferate and to originate Schwann and glial-like cells.In summary, we have demonstrated in this work that multipotent adult precursor cell can be isolated and expanded from two accessible adult tissue sources: skin and adipose tissue. The work described in this paper provides the framework for our attempts to use SKPs or ADSc as autologous adult stem cell population for cell replacement and discovery research.

The treatment of the transsphenoidal sphenopalatine encephalocele in infants has not been thoroughly described in the literature. Pterional and subfrontal transbasal approaches have been reported as the advised treatment for transethmoidal encephalocele, but their feasibility for transsphenoidal encephalocele remains controversial, particularly in neonates. The potential harm to vital structures within the herniated tissue and intraoperative bleeding have been considered the major cause of poor postoperative results. The authors present the case of a full-term newborn with a cleft palate and a large transsphenoidal sphenopalatine encephalocele, which filled the nasopharyngeal space and provided MR imaging evidence of an intralesional pituitary gland. The lesion is unusual, and the extracranial intraoral endoscopic approach with an optimal outcome and sparing of the pituitary tissue has never been described in detail in an infant of this age.

Objective To analyze the risk factors of worst outcome associated with moderate head injury. Methods Data on patients with moderate head injury were collected prospectively in 11 Italian neurosurgical units over a period of 18 months. Patients older than 18 years with blunt head injury and at least one Glasgow Coma Scale (GCS) score between 9 and 13 were enrolled. The outcome was determined at 6 months using the Glasgow Outcome Scale. Results We analyzed 315 patients. Initial computed tomographic scans showed a diffuse injury type I or II in 63%, a mass lesion in 35%, and traumatic subarachnoid hemorrhage in 42% of the patients. The risk of progression toward a mass lesion was 23% when the admission computed tomographic scan showed diffuse injury type I or II. An emergency craniotomy was performed in 22% of the patients, delayed surgery was performed in 14%, and both were performed in 25%. A favorable outcome was obtained in 74% of the patients. When the GCS score was 9 or 10, the predictor of worst outcome was a motor GCS score of 4 or lower (odds ratio [OR], 8.08; 95% confidence interval [CI], 1.22-67.35; P = 0.008), but when the GCS score was 11 to 13, the factors associated with worst outcome were neuroworsening (OR, 3.43; 95% CI, 1.45-8.17; P = 0.002), seizures (OR, 7.94; 95% CI, 1.18-64.48; P = 0.02), and medical complications (OR, 4.24; 95% CI, 1.74-10.33; P = 0.0006). Conclusion There is a high percentage of surgery and worsening on computed tomographic scans in patients with moderate head injury. Neuroworsening, seizures, and medical complications as outcome predictors were more strongly associated with a GCS score of 11 to 13, whereas a low motor GCS score was more outcome-related in patients with GCS scores of 9 and 10.

Hypoxia commonly occurs in solid tumors of the central nervous system (CNS) and often interferes with therapies designed to stop their growth. We found that pediatric high-grade glioma (HGG)-derived precursors showed greater expansion under lower oxygen tension, typical of solid tumors, than normal CNS precursors. Hypoxia inhibited p53 activation and subsequent astroglial differentiation of HGG precursors. Surprisingly, although HGG precursors generated endogenous bone morphogenetic protein (BMP) signaling that promoted mitotic arrest under high oxygen tension, this signaling was actively repressed by hypoxia. An acute increase in oxygen tension led to Smad activation within 30 minutes, even in the absence of exogenous BMP treatment. Treatment with BMPs further promoted astroglial differentiation or death of HGG precursors under high oxygen tension, but this effect was inhibited under hypoxic conditions. Silencing of hypoxia-inducible factor 1α (HIF1α) led to Smad activation even under hypoxic conditions, indicating that HIF1α is required for BMP repression. Conversely, BMP activation at high oxygen tension led to reciprocal degradation of HIF1α; this BMP-induced degradation was inhibited in low oxygen. These results show a novel, mutually antagonistic interaction of hypoxia-response and neural differentiation signals in HGG proliferation, and suggest differences between normal and HGG precursors that may be exploited for pediatric brain cancer therapy.

The efficacy of temozolomide (TMZ) plus radiation therapy (RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Inclusion criteria were age ≥65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. We enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; gross total resection was performed in 174 cases. MGMT was analyzed in 151 persons and was methylated in 56 %. IDH1 was assessed in 100 patients and was mutated in 6 %. Seventy-one patients were treated with RT 40 Gy and 166 with RT 60 Gy. Progression-free survival and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall survival was 19.4 vs 13.8 months for patients treated with RT 60 Gy and 40 Gy (p = 0.02); OS was 17.7 versus 16.1 months for patients treated with gross total resection vs partial surgery (p = 0.02); OS was 21.2 versus 13.6 months for methylated and unmethylated MGMT (p < 0.001). On multivariate analysis, gross total resection, RT 60 Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10 %) had grade 3-4 haematological toxicity during the concomitant treatment. We showed that, in elderly patients in good clinical condition treated with concomitant treatment, standard-course irradiation might be more effective than short-course irradiation. Methylated MGMT remains the most important prognostic factor.

The letter from Professor Bartels calls for the transformation of the EANS into a purely individual membership society. This is perfectly legitimate and raises an important issue, which we in the EANS leadership have discussed at length over the last few years. Quite aside from the specific motion and content raised in the letter, we have encouraged the development of a mature and interactive association, which represents neurosurgeons, primarily in Europe but also worldwide, in a Bbottom-up^ fashion. As such, we fully acknowledge Prof. Bartels’ letter as an important trigger for a serious discussion. Originally founded in 1971 as a federation representing national European neurosurgical societies, the EANS decided just under a decade ago to introduce the opportunity for individual membership. Since then, the EANS has steadily increased its individual membership, while remaining fully committed to serving the needs of its national society members. We now have some 1300 IMs, of which nearly 250 are from non-EANS countries. The remaining ca. 1050 members within EANS countries represent around 15% of all European neurosurgeons, and we have IMs in nearly all EANS member countries. The activity and influence of our individual members has increased significantly in recent years, not only in terms of numbers, but also as a result of increased voting capacity, access to educational material, and other benefits. We believe that this process will continue in the coming years. The role of the EANS in respect of its national society members continues to have tremendous importance. Many members of these societies are unable to join the EANS as IMs for various reasons. Through their national society membership, however, they are both represented within the EANS and exposed to its activities. The fact that EANS represents national societies provides our community with a much stronger voice, and through UEMS activities, affords us significantly more influence upon EU commissions. The role of our JRAAC (Joint Residency Advisory and Accreditation Committee) in dealing with educational progammes and accreditations bridges EANS and UEMS activities and is institutional and related to national societies. The postgraduate system created by the EANS has been adopted by many national societies and is now the acknowledged basis for neurosurgical education within Europe. The close interaction between the Association and its member societies is a significant factor in the strength of the programme. In his letter, Prof. Bartels mentions that Bthe influence of the EANS on national neurosurgical care is nihil. Within our national society, I have never seen or heard of any major development that was initiated by the EANS^. From his perspective in The Netherlands, this may seem true. However, it is not, and has never been, within the mandate of the EANS to initiate developments within national societies. The main reason that EANS cannot influence or initiate new regulations is the EU’s nation states’ decision to retain regulatory powers in respect of health care issues, rather than delegating these to the EU, as is the case in respect of human rights and consumer affairs. As a consequence, the role of EANS initiatives such as JRAAC is limited to making proposals and recommendations. A comparison between the current EANS and the European Union Bwithout its authorities^ is therefore undeserved, since the EANS was founded to support member societies, not to rule over them. * Vladimir Benes vladimir.benes@uvn.cz

Pharmacogenomics, the science of how genetic makeup influences an individual's reaction to drugs, is an innovative tool for providing critical insights into how a patient will respond to a particular treatment. In the present work, we constructed cancer-like tissues to be used as tools for determining the most effective drug for an individual patient. Using tissue engineering strategies, we generated two different solid tumor-like tissues in vitro, a neuronal tumor (meningioma) and a nonmelanoma skin cancer. Samples were tested by both histological and genetic approaches (using a comparative genomic hybridization array, and the relative World Health Organization classification of the samples was compared with the results obtained by the molecular analyses. Our data confirmed the ability of the cells to maintain their phenotype in three-dimensional scaffolds as well as the strong relationship between chromosomal alterations and histological malignancy grades. We then validated the in vitro construction of tumor-like tissues as a potential tool for developing personalized drug treatments.

Despite progress in surgery, radiotherapy, and in chemotherapy, an effective curative treatment of brain cancer, specifically malignant gliomas, does not yet exist. The efficacy of current anti-cancer strategies in brain tumors is limited by the lack of specific therapies against malignant cells. Besides, the delivery of the drugs to brain tumors is limited by the presence of the blood-brain barrier. Nanotechnology today offers a unique opportunity to develop more effective brain cancer imaging and therapeutics. In particular, the development of nanocarriers that can be conjugated with several functional molecules including tumor-specific ligands, anticancer drugs, and imaging probes, can provide new devices which are able to overcome the difficulties of the classical strategies. Nanotechnology-based approaches hold great promise for revolutionizing brain cancer medical treatments, imaging, and diagnosis.

Object. Tumor necrosis factor receptor (TNFR)—associated factors (TRAFs) are a recently established group of proteins involved in the intracellular signaling of the TNFR superfamily members. The TRAFs have been implicated in promoting cell survival through the activation of transcription factor nuclear factor (NF)—κB. The authors investigated the expression of NF-κB, caspase 3, TRAF1, TRAF2, and TRAF-associated NF-κB activator/TRAF—interacting protein (TANK/I-TRAF), a regulator of TRAF activity, in human gliomas. Methods. Tumor samples were obtained in 27 adult patients harboring seven low-grade gliomas, nine anaplastic astrocytomas, and 11 glioblastomas multiforme. The NF-κB activation was analyzed using the electrophoresis mobility shift assay; TRAF1, TRAF2, TANK/I-TRAF, and caspase 3 expression were studied using Western blot analysis. Upregulated NF-κB DNA—binding activity, compared with that in normal brain tissue, was detected in all tumor samples (p = 0.002). The level of NF-κB activity showed some correlation with World Health Organization tumor grades (p = 0.01), even though variable activity levels were demonstrated in relation to tissue heterogeneity, which resulted in a substantial number of outliers in the quantitative analysis. Increased levels of TRAF1, TRAF2, and TANK/I-TRAF were expressed in astrocytomas compared with levels in normal brain tissue (p = 0.02, 0.006, and 0.01, respectively). Conclusions. Data in this study confirm the upregulation of NF-κB in gliomas and reveal a correlation between levels of this transcription factor and tumor grade. A constitutive expression of TRAF1, TRAF2, and TANK/I-TRAF in human gliomas was documented. These proteins are involved in the intracellular signal transduction of the TNFR superfamily and in the control of NF-κB expression and its antiapoptotic activity.

We report 24 patients with a traumatic acute subdural haematoma of the posterior fossa managed between 1997 and 1999 at 8 Italian neurosurgical centres.Each centre provided data about patients' clinico-radiological findings, management, and outcomes, which were retrospectively reviewed.A poor result occurred in 14 patients (58.3%). Ten patients (41.7%) had favourable results. Patients were divided into two groups according to their admission Glasgow Coma Scale (GCS) scores. In Group 1 (12/24 cases; GCS score,or =8), the outcome was favourable in 75% of cases. In Group 2 (12/12 cases; GCS score,8), the outcome was poor in 91.6% of cases. Nineteen patients underwent posterior fossa surgery. Factors correlating to outcome were GCS score, status of the basal cisterns and the fourth ventricle, and the presence of supratentorial hydrocephalus. Multivariate analysis showed significant independent prognostic effect only for GCS score (P0.05).acute posterior fossa subdural haematomas can be divided into two distinct groups: those patients admitted in a comatose state and those with a moderate/mild head injury on admission. Comatose patients present usually with signs of posterior fossa mass effect and have a high percentage of bad outcomes. On the contrary, patients admitted with a GCS of 8 or higher are expected to recover. In these patients the thickness of the haematoma (1 cm) seems to be a guide to indicate surgical evacuation of the haematoma.

OBJECTIVE We report 81 patients with a traumatic intracerebellar hemorrhagic contusion or hematoma managed between 1996 and 1998 at 13 Italian neurosurgical centers. METHODS Each center provided data about patients' clinicoradiological findings, management, and outcomes, which were retrospectively reviewed. RESULTS A poor result occurred in 36 patients (44.4%). Forty-five patients (55.6%) had favorable results. For the purpose of data analysis, patients were divided into two groups according to their admission Glasgow Coma Scale (GCS) scores. In Group 1 (39/81 cases; GCS score, ≥8), the outcome was favorable in 95% of cases. In Group 2 (42/81 cases; GCS score, CONCLUSION This study describes clinicoradiological findings and prognostic factors regarding traumatic cerebellar injury. A general consensus emerged from this analysis that a conservative approach can be considered a viable, safe treatment option for noncomatose patients with intracerebellar clots measuring less than or equal to 3 cm, except when associated with other extradural or subdural posterior fossa focal lesions. Also, a general consensus was reached that surgery should be recommended for all patients with clots larger than 3 cm. The pathogenesis, biomechanics, and optimal management criteria of these rare lesions are still unclear, and larger observational studies are necessary.